2-Halobenzoic acids are important as starting material for the manufacture of pharmaceuticals and pesticides. As processes for producing 2-halobenzoic acids, the following have been disclosed so far: (1) a process of subjecting a 2-aminobenzoic acid to Sandmeyer reaction (J. Am. Chem. Soc., 1923, 51, 1971), (2) a process of utilizing the lithiation of a benzoic acid by the use of an alkyllithium (J. Org. Chem., 1989, 54, 4372), (3) a process of using iodine-fuming sulfuric acid (Org. Synth., III, 796 (1955)), and (4) a process of using thallium (III) trifluoroacetate (J. Am. Chem. Soc., 2176 (1970), etc. Apart from above, there is known a process of introducing a halogen atom into benzene ring by the use of a palladium catalyst. In this process, however, the substrate must have (5) a functional group in which a hetero atom such as nitrogen atom or the like is directly linked to a benzene ring as a substituent, as mentioned in J. Chem. Soc. Commun., 1970, 417 or (6) a functional group in which a hetero atom is attached to the benzyl position as a substituent as mentioned in J. Organometal. Chem., 262, C11 (1984), and these processes mostly require to use a stoichiometric amount of palladium. Although some of these processes requires to use palladium only in a catalytic amount, the “catalytic amount” referred to therein is not so small but it is still as large as about 5–20% based on the amount of substrate. On the other hand, there is also known (7) a process of introducing a carbon-substituent group into benzene ring of benzoic acids substrates by the use of a palladium catalyst, as mentioned in J. Org. Chem., 1998, 63, 5211, however, no case of halogenation is reported in this type of reactions, and a catalyst cycle can be formed only by combining a copper salt with oxygen.
All these processes, however, are disadvantageous in that the process (1) entails a danger of explosion and forms a large quantity of acidic waste water; the process (2) requires a low temperature of 0° C. or below; the process (3) forms a large quantity of sulfuric acid as waste water and is insufficient in the regioselectivity; the process (4) requires to use the highly toxic metal at least in an equivalent amount to the starting material; the processes (5) and (6) are not applicable to benzoic acids or require to use an expensive palladium catalyst in a large amount, and the process (7) is not applicable to catalytic halogenation.
As above, all the prior processes have been industrially disadvantageous from the viewpoint of safety or because of the problem of waste water, or have been unable to realize halogenation at the specific position of benzoic acid. Thus, it is an object of the present invention to establish a process for regioselective halogenation reaction which allows the reaction to progress under mild conditions by the use of a catalytic amount of metal.
With the aim of solving the above-mentioned problem, the present inventors conducted extensive studies. As a result, a regioselective halogenation was achieved by reacting a benzoic acid or its derivative represented by general formula (II) with a halogenating agent in the presence of a catalytic amount of palladium catalyst, in the presence or absence of an appropriate inert solvent. Based on the result mentioned above, the present invention was accomplished.